US20090149488A1

US20090149488A1 - Tetrahydroprotoberberine Compounds, the Synthetic Method and the Use Thereof

Info

Publication number: US20090149488A1
Application number: US11/988,441
Authority: US
Inventors: Jianfeng Li; Aixiang Liu; Xinjian Chen; Guozhang Jin; Tiema Yan; Rongxia Zhang; Yi Zhu; Yanjun Pan; Jingshan Shen; Jingkang Shen
Original assignee: Shanghai Institute of Materia Medica of CAS; Topharman Shanghai Co Ltd
Current assignee: Shanghai Institute of Materia Medica of CAS; Topharman Shanghai Co Ltd
Priority date: 2005-07-08
Filing date: 2006-07-07
Publication date: 2009-06-11
Also published as: WO2007006212A1; US8501762B2; EP1904493A4; EP1904493B1; EP1904493A1

Abstract

The present invention relates to tetrahydroprotoberberines of the formula (I) and the physiologically acceptable salts thereof. The invention also relates to the use of the compounds of the formula (I) or pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with dopamine receptor ligand, such as schizophrenia.

Description

TECHNICAL FIELD

The present invention relates to novel tetrahydroprotoberberines. The compounds possess valuable therapeutic properties and are suitable, especially, for treating diseases that respond to modulation of dopamine receptors, such as schizophrenia, parkinsonism, hyperactivity disorder or migraine et. al.

BACKGROUND ART

Recently, the pathogenesis of schizophrenia has been suggested to involve dysfunction of dopamine D₁receptors in the medial prefrontal cortex (mPFC). Which is resulted in dopamine D₂receptor hyperactivity in subcortical regions such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). D₁receptors dysfunction is involved in the negative symptoms of schizophrenia whereas the D₂receptors hyperactivity results in the positive symptoms of this disorder. According to this new hypothesis, an effective antipsychotic drug should have both D₁receptor agonist and D₂receptor antagonist dual actions.
Tetrahydroprotoberberine analogues (THPBs) have this dual actions, including l-Stepholidine (l-SPD) and l-chloroscoulerine (ZL94112235.2, CN03151464.2). l-SPD is an active ingredient of the Chinese herb Stephania. l-CSL is a derivative of l-SPD. In preliminary clinic studies, l-SPD showed favorable activity and few side effects in the treatment of schizophrenia. So, the efficacy of THPBs for neuron system disease especially schizophrenia merits further investigation.

DISCLOSURE OF THE INVENTION

The invention is based on the object of providing compounds of THPBs, as well as its pharmacologically acceptable salts and solvates, which act as highly affinity dopamine receptor ligands.
The present invention also relates to a preparation method of compounds of THPBs.
The present invention also relates to a method for treating disorder which respond to influencing by dopamine D₁and D₂receptor. And a method comprise administering an effective amount of at least one THPBs of the formula (I) and/or at least one physiologically acceptable salt of formula (I) to a subject in need thereof.
The present invention relates to the compounds of formula (I), pharmacologically acceptable salts and solvates:
Wherein
R is H, halogen or cyano;
Each of R₁, R₃, R₄is selected from H, C₁˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆, SO₂NR₉R₁₀, or R₁and R₂together form (CH₂)_n, n is 1 or 2; when R₁, R₃, R₄is C₁˜C₁₂alkyl, the alkyl is saturated or unsaturated alkyl, linear chain C₁˜C₁₂alkyl, branched chain C₁˜C₁₂alkyl, C₁˜C₁₂cycloalkyl, C₁˜C₁₂alkyl substituted by aryl, COOR₆or CONR₉R₁₀; when R₁, R₃, R₄is amino acid or N-protected amino acid, which is D-, L- or DL-amino acid or N-protected amino acid; the protecting groups is selected from Boc, Cbz or other protected group used in amino acid; R₆is selected from H, C₁˜C₃alkyl or alkyl substituted by aryl; R₇is selected from C₁˜C₁₂alkyl, alkyl substituted by (CH₂CH₂O)_nR₆(n=1˜3), alkoxy, COR₈, (CH₂)_nNR₉R₁₀, substituted aryl, unsubstituted aryl, heterocyclic radical selected from imidazolyl, pyrazolyl, pyrrolidinyl, pyridinyl; when R₇is C₁˜C₁₂alkyl, the alkyl is saturated or unsaturated alkyl, linear chain C₁˜C₁₂alkyl, branched chain C₁˜C₁₂alkyl, C₁˜C₁₂cycloalkyl, C₁˜C₁₂alkyl substituted by carbonyl, phenyl, substituted phenyl or substituted aryl heterocyclic radical; R₈is selected from H, alkyl, alkoxy or aryl; R₉and R₁₀is selected independently from H, C₁˜C₄alkyl substituted by C₃˜C₅cycloalkyl or C₁˜C₄alkoxy, or form heterocyclic radical selected from azacyclobutyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl;
R₂is selected from H, C₁˜C₃alkyl, or R₁and R₂together form (CH₂)_n, n is 1 or 2;
R₅is H, O, C₁˜C₃alkyl, substituted C₁˜C₃alkyl, halogen or aryl, or there is not R₅.
In the definition mentioned above, halogen is F, Cl, Br or I; any two of R₁, R₂, R₃, R₄are same or different group mentioned above.
In particular, when R is H, R₁˜R₄is limited as follow:
When R₁is H and R₂═R₃═CH₃, R₄is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀.
When R₁is H and R₂═R₄═CH₃, R₃is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀.
When R₁is CH₃, R₂is CH₃, and one of R₃and R₄is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀.
When R₁is CH₂Ph, one of R₃and R₄is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀.
When R₁and R₂together form CH₂, R₃or R₄can't be selected from H, CH₃, C₂H₅or COCH₃at the same time.
When R is halogen, the compounds described in this invention exclude followed known compounds:

2,9-dihydroxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,10-dihydroxy-3,9-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,3,9,10-tetramethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,9-dihydroxy-3,10-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,10-dihydroxy-3,9-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
3,9-dihydroxy-2,10-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
9,10-dihydroxy-2,3-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,3,9,10-tetramethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,9-dihydroxy-3,10-dimethoxy-12-fluoro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,9-dihydroxy-3,10-dimethoxy-12-iodo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,3-methylenedioxyl-9-hydroxy-10-methoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,3-methylenedioxyl-9-hydroxy-10-methoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine.

Formula (I) has one or several chiral carbons. So the chiral isomers exist, including enantiomers, unenantiomers or its mixture. This invention including the R—, and S— enantiomers and its mixture. The enantiomer can be separated by optical resolution with chemical method or separated by chiral HPLC. It also can be obtained by asymmetry synthesis.
The present invention relates to radioactivity derivatives of formula (I), which is suitable for biological studies.
The present invention also relates to the physiologically acceptable acid addition salts and alkali derivatives of formula (I). The acid addition salts are salts of the compounds of formula (I) with acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, organic sulfonic acid. The alkali derivatives is salts obtained by reacting the compounds of formula (I) with alkali, especially alkali metal derivatives, including natrium or potassium derivatives.
In the preferred embodiments of the compounds of formula (I), R₁is H, COR₇, amino acid, or R₁and R₂together forms CH₂; R₇is selected from C₁˜C₁₂alkyl, COR₈, alkoxy, or alkyl substituted by (CH₂CH₂O)_nR₆(n=1˜3); R₆is H, C₁˜C₃alkyl or alkyl substituted by aryl; R₈is alkoxy; R₂is H, methyl, or R₂and R₁together form CH₂; R₃is H, COR₇or amino acid; R₄is H, methyl or amino acid; R is H, Cl or F.
The following compounds of formula (I) are particularly preferred:

2-hydroxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,9-diacetoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2-hydroxy-3,10-dimethoxy-9-(2-hydroxy-ethoxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2-hydroxy-3,10-dimethoxy-9-ethoxycarbonyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2-benzyloxy-3,10-dimethoxy-9-phenylalanyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,9-diacetoxy-3,10-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,9-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy}-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2-hydroxy-3,10-dimethoxy-9-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy}-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,3,9,10-tetrahydroxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
(−)-2,9-diacetoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo [a,g]quinolizine;
(−)-2,10-diacetoxy-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
(−)-2-hydroxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;
2,3-methylenedioxyl-9,10-dimethoxy-12-fluoro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine.

The present invention also related to the method of preparing the compounds of formula (I) and its derivatives.
The compounds of the formula (I) can be prepared by analogy to methods which are well known in the literatures. A preferred method for the preparation of compounds (I) is outlined below:
1. Preparation from Formula (II):
Compound of formula (II) is reacted with compound of formula (III) to prepare compound of formula (I):
R₃Y (III)
Wherein R₃is defined as described above, Y is halogen or hydroxy.
(1) Compound of formula (II) is reacted with R₃Cl or R₃Br. The temperature is in the range of 0° C.-100° C. The reaction is catalysted by appropriate alkali. In detail, in the present of inorganic alkali (for example: NaOH, KOH, CsOH, Ba(OH)₂, Mg(OH)₂, Ca(OH)₂, KHCO₃, K₂CO₃, Na₂CO₃, Cs₂CO₃) or organic alkali (for example: sodium alkoxide, NEt₃, N(C₄H₉)₃, N(C₃H₇)₃, et al), the mixture was stirred at 0-100° C. for 2-24 hours to give compound of formula (I). The solvent can be selected in alcohol (for example: methanol, ethanol, isopropanol, C₄H₉OH, iso-C₄H₉OH, t-C₄H₉OH, C₅H₁₁OH, iso-C₅H₁₁OH), the mixture solution of alcohol and water (alcohol:water=5:9.5-9.5:0.5, V:V) or other solvent (for example: DMF, CH₂Cl₂, DMSO, THF, dioxane, pyrrolidinylone, acetone and CH₃OCH₂CH₂OCH₃).
(2) Compound of formula (II) is treated with R₃COCl, R₃CO)₂O or R₃CO)₂O. The reaction carry through in the present of appropriate alkali at 0-100° C. In detail, in the present of inorganic alkali (for example: NaOH, KOH, CsOH, Ba(OH)₂, Mg(OH)₂, Ca(OH)₂, KHCO₃, K₂CO₃, Na₂CO₃, Cs₂CO₃) or organic alkali (for example: pyridine, NEt₃, N(C₄H₉)₃, N(C₃H₇)₃, et al), the mixture was stirred at 0-100° C. for 2-8 hours to give compound of formula (I). The solvent can be selected in pyridine, DMF, CH₂Cl₂, DMSO, THF, dioxane and pyrrolidone derivatives. The catalyst such as DMAP is added according the reaction conditions.
(3) Compound of formula (II) is reacted with ClSO₂R₆, or ClSO₂NR₉R₁₀. The reaction carry through in the present of appropriate alkali at 0° C. to room temperature. In detail, in the present of inorganic alkali (for example: NaOH, KOH, CsOH, Ba(OH)₂, Mg(OH)₂, Ca(OH)₂, KHCO₃, K₂CO₃, Na₂CO₃, Cs₂CO₃) or organic alkali (for example: pyridine, NEt₃, N(C₄H₉)₃, N(C₃H₇)₃, et al), the mixture was stirred at 0-100° C. for 2-8 hours to give compound of formula (I). The solvent can be selected in pyridine, DMF, CH₂Cl₂, DMSO, THF, dioxane and pyrrolidone derivatives.
(4) Compound of formula (II) is reacted with N-protected amino acid. The reaction of THPBs with amino acid can be finished through the procedure of esterification. For example, starting from the chloroacetyl derivatives of amino acid to give the desired compound. Another method is treat THPBs and amino acid in the present amino acid catalyst. In detail, the reaction is carried through at 0° C. to room temperature to give compound of formula (I). The solvent can be selected in CH₂Cl₂, DMF or THF. The catalyst can be selected in DCC, CDI, EDCI or other coupled reagent, accompanied by HOBt or DMAP.
(5) The deprotection of N-deprotected amino acid derivatives of THPBs (II) is carried through in the present of acid. In detail, the reaction is carried through at 0° C. to room temperature in the present of inorganic acid (for example: HCl, H₂SO₄, et al) or organic acid (for example: toluenesulfonic acid, CF₃COOH, AcOH, et al). The solvent can be selected in CH₂Cl₂, THF, et al.
(6) When R₁═H, compound of formula (I) was obtained by hydrogenating the compound of formula (II) (R₁═CH₂Ph) in the present of catalyst in order to avoid the hydrogenate of halogen in THPBs. In detail, compound of formula (II) is hydrogenated in the present of Raney-Ni at 0-40° C. for 1-10 hours to give compound of formula (I). The solvent is alcohol (for example: methanol, ethanol, isopropanol, et al) or the mixture solution of alcohol and water.
Compound of formula (II) is given as follow:
A) When R₂═R₄═CH₃and R═Cl, that is 2-benzyloxy-3,10-dimethoxy-9-hydroxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine (compound IIA). Intermediate IIA is preparation according to the method reported in literature (CN03151464.2), and (−)-IIA is obtained through resolution from IIA (CN03151464.2).
B) When R₂, R₄is other substituted groups, the hydroxyl derivatives of THPBs can be obtained by debenzyloxy or demethyl reaction of compound of formula (II) (R₂═R₄═CH₃) in the present of BBr₃. This compound is esterificated, etherificated, coupled with amino acid or demethylatied to provide the compound of formula (II). The procedure is described above.
2. Preparation from Formula (IV):
R is Cl, H.
Compound of formula (IV) is treated with compound of formula (III) to preparation formula (I):
R₁Y (or R₃Y) (III)
Wherein R₁(or R₃) is definited as described above, Y is halogen or hydroxy.
(1) Compound of formula (IV) is react with R₁Cl or R₁Br. The procedure is the same as the synthetic procedure described in the reaction of compound of formula (II) with R₃Cl or R₃Br. The structure of compound of formula (I) is different according the amount of compound of formula (III) and the activity of the hydroxy of compound of formula (IV).
(2) Compound of formula (IV) is reacted with R₁COCl, (R₁CO)₂O or (R₃CO)₂O. The procedure is the same as the synthetic procedure described in the reaction of compound of formula (II) with R₁COCl, (R₁CO)₂O or (R₃CO)₂O. The structure of compound of formula (I) is different according the amount of compound of formula (III) and the activity of the hydroxy of compound of formula (IV).
Compound of formula (IV) is given as follow:
(1) When R is Cl, compound of formula (IV) is given as follow:
Compound of formula (II) (R₂═R₄═CH₃, R═Cl) was debenzylization with common method to give compound of formula (VI) (R═Cl). The methods are hydrogenate or hydrolysis by acid. In detail, compound of formula (II) is hydrogenated in the present of Raney-Ni at 0˜40° C. for 1˜10 hours to give compound of formula (VI) (R═Cl). The solvent is alcohol (for example: methanol, ethanol, isopropanol, et al) or the mixture solution of alcohol and water. Alternatively, compound of formula (II) is heat with acid (for example: HCl, H₂SO₄, HBr, et al) to debenzylate. The solvent is acid (HCOOH, AcOH, et al) or alcohol (such as ethanol).
(2) When R is H, compound of formula (IV) is given as follow:
Compound of formula (II) (R₂═R₄═CH₃, R═Cl) is hydrogenated in the present of Pd—C under high pressure to give formula (IV) (R═H). In detail, compound of formula (II) is hydrogenated at 20-60° C. for 3˜24 hours in the present of acid (for example: HCl/H₂O, H₂SO₄/H₂O, HBr/H₂O, et al) to give compound of formula (IV) (R═H). The solvent is alcohol (for example: methanol, ethanol, isopropanol, et al) or other solvent (DMF, DMSO, THF, et al).
3. Preparation from Formula (V):
Compound of formula (V) is natural product l-SPD, isolated from plants. Staring from l-SPD, the compound of formula (I) can be provided by esterification, etherification, coupling with amino acid or demethylation. The procedure is described above.

4. The Preparation of N-Substituted Derivatives of Formula (I)

The free base of compound of formula (I) is reacted with alkyl halide (for example; CH₃I) or substituted halide alkyl (for example; PhCH₂Br) at room temperature to 100° C., followed by precipitating when cooling, or by separating through column chromatography to give the target product;
5. Preparation from Formula (VI):
Compound of formula (VI) was reacted with HNO₂to give diazo salts, which is react with corresponding reagent to give the compound of formula (I) (R=halogen, cyano).
Compound of formula (VI) can be prepared as follow:
Nitration of compound of formula (I) (R═H) to give nitro derivatives, which is reduced to give compound of formula (VI). The nitro derivatives of compound of formula (I) also can be obtained by cyclization of nitro benzylisoqunoline derivatives.
The physiologically acceptable acid addition salts of formula (I) can be obtained by the conventional methods in the literature. For example, the compound of formula (I) was treated with appropriate acid in appropriate solvent, and the salt can be obtained through evaporating solvents or filtrating.
The compound of formula (I) was treated with appropriate alkali to give physiologically acceptable alkali addition salts.
The pharmacological actions of the compound according to the present invention are detected through the following methods.
1. Dopamine Receptor Binding Studies
The affinities of these compounds on dopamine receptors were evaluated with competitive receptor binding assays (Acta Pharmacol Sin, 1989, 10:104 and Acta Pharmacol Sin, 2003, 24(3): 225-229). The Ki is calculated according the inhibition data tested.
l-CSLMS is S-chloroscoulerine mesylate and CSL is chloroscoulerine.

TABLE 1

Affinities of THPBs for binding to dopamine receptors^a

Example	Inhibition(%) for D₁	Inhibition(%) for D₂

7	100	100.0
8	100.0	93.8
17	97.9	57.4
21	100.0	100.0
23	77.5	44.0
34	99.4	90.7
42	96.2	39.7
44	100.0	93.3
47	100.0	77.4
50	100.0	58.5
63	95.2	—

^aInhibition(%) data was tested at 1 × 10⁻⁵mol/L

TABLE 2

Ki values of THPBs for bingding to dopamine receptors

Ki

Example	D₁(nM)	D₂(μM)

l-CSLMS	—	1.7 ± 0.5
CSL	6.1 ± 3.0	—
7	10.7 ± 1.0	6.9 ± 1.5
21	2.6 ± 0.7	—
34	51.8 ± 32.2	10.6 ± 2.6
42	35.4 ± 4.4	14.9 ± 0.2
43	403.5 ± 188.3	—

2. 6-OHDA-Lesioned Rats Rotation Test
Some of the compounds were evaluated on 6-OHDA-lesioned rats model. In this model, compounds of example 7, 44 and 48 exhibit positive effects at 10 mg/kg.
3. PCP-Induced Immobility Test in Mice
Phencyclidine(PCP)-induced immobility test in mice was selected as the model to evaluate the antipsychotic effect of some compounds of the present invention (Br J Pharmacol, 1995, 116: 2531-2537). The dose is selected according the ED₅₀of l-CSLMS. Given PCP, immobility times of mice was increased, whereas the active compound can decrease the immobility time. At 20 mg/kg (i.g.), the immobility time of compound of example 47 is 54.9±19 s, and the immobility time of l-CSLMS is 48.0±27 s, which has statistically significant differences (P<0.05) compared to PCP group (78.1±28 s).
The present invention therefore relates to compounds of formula (I) and physiologically acceptable salts.
The present invention therefore relates to a pharmaceutical composition which comprises at least one compound of the formula (I) and/or at least one physiologically acceptable addition salt of (I), together with physiologically acceptable carriers and/or auxiliary substances.
The present invention also relates to a method for treating disorder which respond to influencing by dopamine D₁and D₂receptor. And a method comprise administering an effective amount of at least one THPBs of the formula (I) and/or at least one physiologically acceptable addition salt of (I) to a subject in need thereof.
The present invention also relates to all the new intermediates described in this invention.

THE PREFERABLE EMBODIMENTS OF THE INVENTION

The following examples serve to explain the invention without limiting it.
The compounds were characterized either via ¹H NMR or MS.
The compound in formula (II), when R₂═R₄═CH₃, R═Cl, i.e. the intermediate 2-benzyloxy-3,10-dimethoxy-9-hydroxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo [a,g]quinolizine (compound IIA), which is prepared according to the method reported in literature (CN03151464.2), (−)-IIA is obtained through the resolution from IIA (CN03151464.2).

Preparation 1

2-benzaloxy-3,10-dimethoxy-9-hydroxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine (compound IIA)

1-(2′-chloro-4′-methoxy-5′-hydroxy)benzyl-6-methoxy-7-benzyloxy-1,2,3,4-tetrohydroisoquinolin (compound of formula VII) (103 g, 0.235 mol) was added methanol (5150 ml) and hydrochloric acid to adjust pH1-2. The mixture was then added 37% HCHO (3090 ml) and water (2000 ml). After stirring for 2 days, the solvent was evaporated and the residue was neutralized with NaHCO₃to pH 9. The aqueous was extract with CHCl₃. The combined organic layers was dried and concentrated to give desired compound (103 g, 97.3%).

Example 1

2,9-dihydroxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (1.0 g, 2.2 mmol) was dissolved in CH₃OH, and Raney-Ni was added. The mixture was stirred for 2-5 hours under hydrogen at normal pressure and room temperature. After filtering the catalyst, the filtrate was concentrated to give the product as pink powder (0.73 g, 90.8%). That is chloroscoulerine. mp 136˜138° C. ¹HNMR (CDCl₃) δ: 2.57˜2.70 (3H, m, CH₂), 3.09˜3.22 (2H, m, CH₂), 3.21˜3.39 (1H, dd, CH₂), 3.45˜3.54 (5H, m, CH₂, N—CH and CH₃OH), 3.85 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.20 (1H, d, CH₂), 5.50 (1H, brs, OH), 5.63 (1H, brs, OH), 6.60 (1H, s, ArH), 6.80 (1H, s, ArH), 6.89 (1H, s, ArH).

Example 2

2,9-dihydroxy-3,10-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine hydrochloride

Compound IIA (2.0 g, 4.4 mmol) was dissolved in CH₃OH (200 ml), adding 1 mol/L hydrochloric acid (5 ml) and 10% Pd—C (0.3 g). The mixture was hydrogenated under pressure at 50-60° C. for 12 hours. After the raw material disappeared detected with TLC, filtering the catalyst, the filtrate was concentrated to give the product as beige powder (1.5 g, 93%). That is scoulerine, which can be used as a intermediate for next step. mp 246° C. ¹HNMR (DMSO-d₆) δ: 2.46˜2.60 (3H, m, CH₂), 3.13 (1H, m, CH₂), 3.14˜3.30 (4H, m, CH₂or N—CH), 3.74 (3H, s, Ar—OCH₃), 3.76 (3H, s, Ar—OCH₃), 4.03 (1H, d, CH₂), 6.59 (1H, d, ArH), 6.64 (1H, s, ArH), 6.70 (1H, s, ArH), 6.78 (1H, d, ArH).

Example 3

2-benzyloxy-3,10-dimethoxy-9-benzoyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.5 g, 1.1 mmol) was dissolved in CH₂Cl₂(30 ml), adding benzoyl chloride (0.2 g, 0.17 ml, 1.4 mmol) and triethylamine (0.19 ml). The mixture was stirred at room temperature for 5 hours. After the raw material disappeared detected with TLC, the mixture was poured into water, adding 1 mol/L NaOH. The aqueous phase was extracted three times with CH₂Cl₂. The combined organic phase were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=1/5) and recrystallized with ethyl acetate/petroleum ether to give the product as pale yellow powder. mp 170-172° C.

Example 4

2-hydroxy-3,10-dimethoxy-9-benzoyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 3 (0.183 g, 0.33 mmol) was add CH₃OH (15 ml) and Raney-Ni. The mixture was hydrogenated at room temperature for 1 hours. The mixture was filtered, and the filtrate was concentrated to give the product as yellow-green solide (0.16 g). The solide was recrystallized with ethyl acetate/petroleum ether to give pale yellow powder (0.041 g, 26.7%). mp 162˜164° C. ¹HNMR (CDCl₃) δ: 2.57˜2.71 (3H, m, CH₂), 3.08˜3.12 (2H, m, CH₂), 3.36˜3.58 (3H, m, CH₂and N—CH), 3.79 (3H, s, Ar—OCH₃), 3.87 (3H, s, Ar—OCH₃), 4.02 (1H, br, CH₂), 5.55 (1H, s, Ar—OH), 6.59 (1H, s, ArH), 6.89 (1H, s, ArH), 6.95 (1H, s, ArH), 7.51˜7.56 (2H, m, PhH), 7.65˜7.67 (1H, m, PhH), 8.22˜8.24 (2H, m, PhH). MS (EI) m/z: 464 (M−1), 360, 344, 178, 105 (base), 77.

Example 5

2,9-dibenzoyloxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 1 (0.15 g, 0.41 mmol) was suspend on CH₂Cl₂(20 ml), adding benzoyl chloride (0.22 ml) and triethylamine (0.26 ml). The mixture was stirred at room temperature for 7 hours. Then the reaction was diluted with CH₂Cl₂(10 ml), followed by adding 0.5 mol/L n NaOH. The aqueous phase was extracted two times with CH₂Cl₂. The combined organic layers were washed with water, brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=1/4) to give pale yellow powder (0.18 g, 76.2%). The analytic sample was recrystallized by ethyl acetate/petroleum ether. mp 152˜154° C. ¹HNMR (CDCl₃) δ: 2.61˜2.76 (3H, m, CH₂), 3.14 (2H, m, CH₂), 3.36˜3.41 (2H, m, CH₂and N—CH), 3.61 (1H, m, CH₂), 3.78 (3H, s, Ar—OCH₃), 3.80 (3H, s, Ar—OCH₃), 4.09 (1H, br, CH₂), 6.75 (1H, s, ArH), 6.95 (1H, s, ArH), 7.11 (1H, s, ArH), 7.50˜7.56 (4H, m, PhH), 7.62˜7.67 (2H, m, PhH), 8.23˜8.25 (4H, m, PhH).

Example 6

2-benzyloxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.5 g, 1.1 ml) was dissolved in pyridine (10 ml), adding acetyl anhydride (1 ml). The mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated to small volume and poured into water, adjusting to pH 8 with saturated NaHCO₃. The aqueous phase was extracted three times with CH₂Cl₂. The combined organic layers were washed with water, brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was discolored by activated carbon and recrystallized with CH₂Cl₂/hexane to give product (0.246 g, 45%). mp 150˜152° C. ¹HNMR (CDCl₃) δ: 2.33 (3H, s, COCH₃), 2.49˜2.71 (3H, m, CH₂), 3.12˜3.15 (3H, m, CH₂), 3.39˜3.52 (2H, m, CH₂and N—CH), 3.80 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 3.98 (1H, d, CH₂), 5.16 (2H, q, Ph—CH₂), 6.63 (1H, s, ArH), 6.76 (1H, s, ArH), 6.90 (1H, s, ArH), 7.26˜7.32 (1H, m, PhH), 7.35˜7.39 (2H, t, PhH), 7.45˜7.47 (2H, d, PhH).

Example 7

2-hydroxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 6 (0.070 g, 0.114 mmol) was add CH₃OH (15 ml) and Raney-Ni. The mixture was hydrogenated at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated to give the product as pale yellow oil. The oil was recrystallized with ethyl acetate/petroleum ether (1/3) to give pale yellow powder (0.022 g, 38.4%). mp 191˜192° C. Anal: Cacul: C, 62.45%; H, 5.49%; N, 3.47%; test: C, 62.19%; H, 5.41%; N, 3.22%. ¹HNMR (CDCl₃) δ: 2.34 (3H, s, COCH₃), 2.58˜2.69 (3H, m, CH₂), 3.10˜3.15 (2H, m, CH₂), 3.33˜3.43 (2H, m, CH₂and N—CH), 3.52˜3.56 (1H, brd, CH₂), 3.80 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 3.99 (1H, d, CH₂), 5.54 (1H, s, Ar—OH), 6.59 (1H, s, ArH), 6.87 (1H, s, ArH), 6.91 (1H, s, ArH). MS (EI) m/z: 405 (M+2), 403 (M⁺), 360, 344 (
), 186, 149, 91.

Example 8

2,9-diacetoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine acetate

A product obtained in Example 1 (0.2 g, 0.55 mmol) was dissolved in pyridine (10 ml), adding acetyl anhydride (1 ml). The mixture was stirred at room temperature overnight. The mixture was concentrated to small volume under reduced pressure. The solution was adding water (5 ml) slowly with stirring. The solid precipitated was collected by filtration and dryed at 50° C. to give gray powder (0.151 g, 61.3%). mp 205˜206° C. ¹HNMR (CDCl₃) δ: 2.34 (6H, 2 s, 2×COCH₃), 2.60˜2.75 (3H, m, CH₂), 3.11˜3.16 (2H, m, CH₂), 3.28˜3.42 (2H, m, CH₂), 3.53˜3.57 (1H, m, CH₂and N—CH), 3.80 (3H, s, Ar—OCH₃), 3.82 (3H, s, Ar—OCH₃), 3.99 (1H, d, CH₂), 6.70 (1H, s, ArH), 6.90 (1H, s, ArH), 6.97 (1H, s, ArH). MS (EI) m/z: 445 (M⁺), 444 (M−1), 386 (base), 184, 176, 77.

Example 9

2-benzyloxy-3,10-dimethoxy-9-cinnamoyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.3 g, 0.66 mmol) was dissolved in CH₂Cl₂(20 ml), adding cinnamyl chloride (0.132 g, 0.79 mmol) and triethylamine (0.11 ml). The desired product was obtained following the synthetic procedure described in Example 3. The crude solid was recrystallized with CH₂Cl₂/hexane to give beige product (0.206 g, 53.3%). mp 198˜200° C. ¹HNMR (CDCl₃) δ: 2.86˜3.01 (3H, m, CH₂), 3.41˜3.57 (3H, m, CH₂and N—CH), 3.73˜3.79 (2H, m, CH₂), 4.14 (3H, s, Ar—OCH₃), 4.21 (3H, s, Ar—OCH₃), 4.35 (1H, d, CH₂), 5.50 (2H, q, PhCH₂), 6.96 (1H, s, ArH), 7.01 (1H, d, CH═R), 7.12 (1H, s, ArH), 7.59 (1H, s, ArH), 7.63˜7.82 (8H, m, PhH), 7.92˜7.95 (2H, m, PhH), 8.23 (1H, d, CH═R).

Example 10

2-hydroxy-3,10-dimethoxy-9-(3-phenyl-propionyloxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 9 (0.06 g, 0.10 mmol) suspend on CH₃OH (10 ml), adding Raney-Ni. The mixture was hydrogenated at room temperature for 4 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=1/4) to give white powder (0.034 g, 51.8%). ¹HNMR (CDCl₃) δ: 2.47˜2.68 (3H, m, CH₂), 2.92˜3.12 (6H, m, CH₂), 3.19˜3.24 (1H, m, CH₂), 3.29˜3.36 (1H, dd, CH₂), 3.46˜3.51 (1H, dd, CH₂and N—CH), 3.76 (3H, s, Ar—OCH₃), 3.78 (1H, d, CH₂), 3.88 (3H, s, Ar—OCH₃), 5.51 (1H, s, Ar—OH), 6.59 (1H, s, ArH), 6.86 (1H, s, ArH), 6.88 (1H, s, ArH), 7.21˜7.35 (5H, m, PhH).

Example 11

2,9-dicinnamoyloxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 1 (0.2 g, 0.55 mmol) suspend on CH₂Cl₂(20 ml), adding cinnamyl chloride (0.28 g, 1.68 mmol) and triethylamine (0.24 ml). The mixture was stirred at room temperature for 7 hours. Then the mixture was poured into water, adjusting to pH 8 with saturated NaHCO₃. The aqueous phase was extracted with CH₂Cl₂. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography and recrystallized with ethyl acetate/petroleum ether to give pale yellow powder (0.057 g, 16.6%). mp 240˜242° C. ¹HNMR (DMSO-d₆) δ: 2.44˜2.56 (1H, m, CH₂), 2.73˜2.78 (1H, m, CH₂), 3.01˜3.16 (2H, m, CH₂), 3.41 (3H, s, CH₂), 3.54 (1H, dd, N—CH), 3.78 (3H, s, Ar—OCH₃), 3.80 (3H, s, Ar—OCH₃), 4.03 (1H, d, CH₂), 6.84 (1H, d, CH═R), 6.87 (1H, s, ArH), 6.87 (1H, d, CH═R), 7.13 (1H, s, ArH), 7.15 (1H, s, ArH), 7.46˜7.49 (6H, m, PhH), 7.76˜7.83 (4H, m, PhH), 7.85 (1H, d, CH═R), 7.89 (1H, d, CH═R).

Example 12

2-benzyloxy-3,10-dimethoxy-9-propyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.3 g, 0.66 mmol) was dissolved in ethanol, adding 1 mol/L NaOH (5 ml) and propyl bromide (1 ml). The mixture was heating to 50˜60° C. When the reaction was finished, the mixture was concentrated to small volume followed by adding water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=1/5) to give desired product (0.10 g, 30.5%). mp 118˜120° C. ¹HNMR (CDCl₃) δ: 1.03 (3H, t, CH₃), 1.79 (2H, q, CH₂), 2.66˜2.71 (3H, m, CH₂), 3.16˜3.21 (3H, m, CH₂), 3.46˜3.50 (2H, m, CH₂and N—CH), 3.82 (3H, s, Ar—OCH₃), 3.89 (3H, s, Ar—OCH₃), 3.93˜3.97 (2H, t, OCH₂), 4.22 (1H, d, CH₂), 5.17 (2H, q, PhCH₂), 6.64 (1H, s, ArH), 6.79 (1H, s, ArH), 6.84 (1H, s, ArH), 7.26˜7.32 (1H, m, PhH), 7.36˜7.39 (2H, t, PhH), 7.46˜7.48 (2H, d, PhH).

Example 13

2-hydroxy-3,10-dimethoxy-9-propyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 12 (0.045 g, 0.09 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4, 7 or 10. The crude product was purified by silica chromatography to give the product (0.026 g, 70.7%). ¹HNMR (CDCl₃) δ: 1.03 (3H, t, CH₃), 1.79 (2H, q, CH₂), 2.64˜2.71 (3H, m, CH₂), 3.19˜3.53 (5H, m, CH₂and N—CH), 3.82 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 3.93˜3.97 (2H, t, OCH₂), 4.24 (1H, d, CH₂), 5.54 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.85 (1H, s, ArH), 6.88 (1H, s, ArH).

Example 14

2-benzyloxy-3,10-dimethoxy-9-methanesulfonyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.2 g, 0.44 mmol) was dissolved in pyridine (10 ml), adding methanosulfonyl chloride (0.17 ml) with ice bath and stirring overnight. The mixture was concentrated to small volume under reduced pressure. The residual solution was add CH₂Cl₂, following filtration. The filtrate was washed with water, saturated NaHCO₃and brine. The solvent was dried over Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=1/3) to give desired product (0.086 g, 36.7%). The analytic sample was recrystallized by ethyl acetate/petroleum ether. ¹HNMR (CDCl₃) δ: 2.46˜2.69 (3H, m, CH₂), 3.02˜3.20 (3H, m, CH₂), 3.33 (3H, s, SO₂CH₃), 3.49˜3.54 (1H, dd, CH₂and N—CH), 3.62 (1H, d, CH₂), 3.87 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.23 (1H, d, CH₂), 5.16 (2H, q, PhCH₂), 6.63 (1H, s, ArH), 6.75 (1H, s, ArH), 6.92 (1H, s, ArH), 7.29˜7.39 (3H, m, PhH), 7.45˜7.47 (2H, m, PhH).

Example 15

2-hydroxy-3,10-dimethoxy-9-methanesulfonyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 14 (0.035 g, 0.07 mmol) was hydrogenated in the present of Raney-Ni. The desired product as pale yellow powder (0.027 g, 92.9%) was obtained following the synthetic procedure described in Example 1, 4 or 7. ¹HNMR (CDCl₃) δ: 2.58˜2.70 (3H, m, CH₂), 3.04˜3.24, 3.38˜3.39 (3H, m, CH₂), 3.34 (3H, s, SO₂CH₃), 3.54˜3.66 (2H, m, CH₂and N—CH), 3.87 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.25 (1H, d, CH₂), 5.52 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.87 (1H, s, ArH), 6.93 (1H, s, ArH). MS (EI) m/z: 439 (M⁺), 360 (base), 344, 183, 176, 77.

Example 16

2-benzyloxy-3,10-dimethoxy-9-(2-hydroxy-ethoxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.2 g, 044 mmol), 1-chloroethanol (0.16 ml), K₂CO₃(0.38 g, 2.8 mmol), DMF (10 ml) was mixed and heat to 100° C. for 6 hours. The mixture was concentrated to remove DMF and poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether/methanol) and recrystallized with ethyl acetate to give pale yellow crystal (0.157 g, 71.5%). mp 154° C. ¹HNMR (CDCl₃) δ: 2.47˜2.70 (3H, m, CH₂), 2.82 (1H, brs, OH), 3.11˜3.21 (3H, m, CH₂), 3.44˜3.50 (2H, m, CH₂and N—CH), 3.84 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 3.84˜3.88 (2H, br, OCH₂), 3.97˜4.01 (1H, m, OCH₂), 4.11˜4.16 (1H, m, OCH₂), 4.22 (1H, d, CH₂), 5.16 (2H, q, PhCH₂), 6.63 (1H, s, ArH), 6.78 (1H, s, ArH), 6.86 (1H, s, ArH), 7.28˜7.32 (1H, m, PhH), 7.35˜7.39 (2H, m, PhH), 7.45˜7.48 (2H, m, PhH).

Example 17

2-hydroxy-3,10-dimethoxy-9-(2-hydroxy-ethoxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 16 (0.08 g, 0.16 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow powder (0.013 g, 19.9%). mp 184° C. ¹HNMR (DMSO-d₆) δ: 2.28˜2.56 (3H, m, CH₂), 2.71˜2.88 (2H, m, CH₂), 3.04˜3.31 (3H, m, CH₂and N—CH), 3.61 (2H, t, OCH₂), 3.73 (3H, s, Ar—OCH₃), 3.78 (3H, s, Ar—OCH₃), 3.94 (2H, m, OCH₂), 4.18 (1H, d, CH₂), 6.64 (1H, s, ArH), 6.72 (1H, s, ArH), 7.03 (1H, s, ArH).

Example 18

2-benzyloxy-3,10-dimethoxy-9-[2-(2-hydroxy-ethoxy)-ethoxy]-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.5 g, 1.1 mmol), 1-chloroethylglycol (0.45 g, 3.6 mmol), K₂CO₃(0.31 g, 2.2 mmol), DMF (15 ml) was mixed and heat to 100° C. for 20 hours. After filtering K₂CO₃, the mixture was concentrated to remove DMF, followed by pouring into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give yellow needle (0.416 g, 69.6%). The analytic sample was recrystallized with ethyl acetate/petroleum ether. mp 122° C. ¹HNMR (CDCl₃) δ: 2.44˜2.69 (3H, m, CH₂), 3.07˜3.23 (3H, m, CH₂), 3.37˜3.51 (3H, m, CH₂and N—CH), 3.60˜3.71 (5H, m, CH₂) 3.82 (3H, s, Ar—OCH₃), 3.87 (3H, s, Ar—OCH₃), 4.20˜4.24 (2H, m, OCH₂), 4.39 (1H, d, CH₂), 5.16 (2H, q, PhCH₂), 6.62 (1H, s, ArH), 6.77 (1H, s, ArH), 6.83 (1H, s, ArH), 7.29˜7.31 (1H, m, PhH), 7.34˜7.39 (2H, m, PhH), 7.45˜7.47 (2H, m, PhH). MS (EI) m/z: 539 (M−1), 448, 283, 91 (base).

Example 19

2-hydroxy-3,10-dimethoxy-9-[2-(2-hydroxy-ethoxy)-ethoxy]-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 18 (0.116 g, 0.21 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether/methanol) to give yellow solid (0.035 g, 36.2%). ¹HNMR (CDCl₃) δ: 2.61˜2.68 (3H, m, CH₂), 3.18˜3.70 (1H, m, CH₂and N—CH), 3.81 (3H, s, Ar—OCH₃), 3.84 (3H, s, Ar—OCH₃), 4.21 (2H, m, OCH₂), 4.40 (1H, d, CH₂), 6.57 (1H, s, ArH), 6.83 (1H, s, ArH), 6.85 (1H, s, ArH).

Example 20

2-benzyloxy-3,10-dimethoxy-9-ethoxycarbonyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.5 g, 1.1 mmol), ClCOOC₂H₅(2.2 mmol), K₂CO₃(0.46 g, 3.3 mmol), DMF (10 ml) was mixed and heat to 80° C. When the reaction finished, the mixture was concentrated to remove DMF. The residue was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow powder (0.195 g, 33.6%). mp 128° C. ¹HNMR (CDCl₃) δ: 1.39 (3H, t, CH₃), 2.50˜2.68 (3H, m, CH₂), 3.12˜3.19 (3H, m, CH₂), 3.43˜3.50 (2H, m, CH₂and N—CH), 3.82 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.07 (1H, d, CH₂), 4.32 (2H, q, CH₂), 5.16 (2H, q, PhCH₂), 6.63 (1H, s, ArH), 6.76 (1H, s, ArH), 6.90 (1H, s, ArH), 7.28˜7.32 (1H, m, PhH), 7.35˜7.39 (2H, m, PhH), 7.45˜7.48 (2H, m, PhH).

Example 21

2-hydroxy-3,10-dimethoxy-9-ethoxycarbonyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 20 (0.09 g, 0.17 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was recrystallized with CH₂Cl₂/hexane to give pink solid (0.044 g, 59.0%). mp 169˜170° C. ¹HNMR (CDCl₃) δ: 1.39 (3H, t, CH₃), 2.59˜2.68 (3H, m, CH₂), 3.10˜3.16 (2H, m, CH₂), 3.33˜3.56 (3H, m, CH₂and N—CH), 3.82 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.08 (1H, d, CH₂), 4.32 (2H, q, CH₂), 5.52 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.87 (1H, s, ArH), 6.91 (1H, s, ArH). MS (EI) m/z: 432 (M−1), 344 (base), 183, 176, 91.

Example 22

2-benzyloxy-3,10-dimethoxy-9-(N-t-Boc-phenylalanyloxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Method A:
Compound IIA (0.5 g, 1.1 mmol) was dissolved in CH₂Cl₂(20 ml), adding t-Boc-phenylanine (0.88 g, 3.3 mmol) and DCC (0.91 g, 4.4 mmol). The mixture was stirred at room temperature for 6 hours, then cooled in refrigeratory. After filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO₃and cool water. The organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica chromatography to give pale yellow solid (0.722 g, 93.3%). mp 140-141° C. ¹HNMR (CDCl₃) δ: 1.41 (9H, 2×s, 3×CH₃), 2.46-2.68 (3H, m, CH₂), 3.03˜3.19 (4H, m, CH₂), 3.28˜3.49 (3H, m, CH₂and N—CH), 3.79 (3H, d, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.85 (1H, m, CH₂), 4.98 (1H, m, COCH), 5.17 (2H, q, PhCH₂), 6.63 (1H, s, ArH), 6.76 (1H, s, ArH), 6.90 (1H, s, ArH), 7.28˜7.40 (8H, m, PhH), 7.46˜7.48 (2H, m, PhH). MS (EI) m/z: 698 (M⁺), 641, 450, 434 (base), 360, 91.
Method B:
t-Boc-phenylanine (0.177 g, 0.67 mmol) and CDI (0.227 g, 1.4 mmol) was dissolved in dry THF (10 ml) and stirred at room temperature for 30 minutes. Then the solution of compound IIA (0.3 g, 0.66 mmol) in THF (10 ml) was added and stirred for one day. The mixture was evaporated under reduced pressure and purified by Al₂O₃chromatography to give beige solid (0.114 g, 24.6%).

Example 23

2-benzyloxy-3,10-dimethoxy-9-phenylalanyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 22 (0.209 g, 0.30 mmol) was stirred with 10% CF₃COOH in CH₂Cl₂at room temperature for 2 hours. Then the mixture was concentrated and added water, adjusting to pH 8 with saturated NaHCO₃. The aqueous phase was extracted with CH₂Cl₂. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give desired product (0.026 g, 14.5%). ¹HNMR (CDCl₃) δ: 2.46˜2.69 (3H, m, CH₂), 2.96˜3.49 (7H, m, CH₂and N—CH), 3.79 (3H, d, Ar—OCH₃), 3.85 (1H, s, CH₂), 3.88 (3H, s, Ar—OCH₃), 4.03˜4.08 (1H, m, COCH), 5.17 (2H, q, PhCH₂), 6.64 (1H, s, ArH), 6.77 (1H, s, ArH), 6.91 (1H, s, ArH), 7.28˜7.48 (10H, m, PhH).

Example 24

2-hydroxy-3,10-dimethoxy-9-(N-t-Boc-phenylalanyloxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 22 (0.166 g, 0.24 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7 to give pink powder (0.063 g, 43.6%0. mp 110° C. ¹HNMR (CDCl₃) δ: 1.41 (9H, 2×s, 3×CH₃), 2.52˜2.68 (3H, m, CH₂), 3.02˜3.19 (3H, m, CH₂), 3.30˜3.33 (3H, m, CH₂), 3.49˜3.53 (1H, m, CH₂and N—CH), 3.79 (3H, d, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.86 (1H, m, CH₂), 4.98 (1H, m, COCH), 6.59 (1H, s, ArH), 6.87 (1H, s, ArH), 6.90 (1H, s, ArH), 7.27˜7.37 (5H, m, PhH).

Example 25

2-hydroxy-3,10-dimethoxy-9-phenylalanyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 24 was treat with 10% CF₃COOH in CH₂Cl₂. The desired product was obtained following the synthetic procedure described in Example 23.

Example 26

2-benzyloxy-3,10-dimethoxy-9-(N-t-Boc-glycyloxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Method A:
Compound IIA (0.25 g, 0.55 mmol) was dissolved in CH₂Cl₂(20 ml), adding t-Boc-glycine (0.214 g, 1.22 mmol) and DCC (0.407 g, 1.98 mmol). The mixture was stirred at room temperature for 24 hours, then cooled in refrigeratory. After filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO₃and cool water. The organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The crude product was dissolved with ethyl acetate and filtered. The filtrate was recrystallized with ethyl acetate to give pale yellow solid (0.238 g, 70.8%). mp 160° C. ¹HNMR (CDCl₃) δ: 1.46 (9H, s, 3×CH₃), 2.49˜2.69 (3H, m, CH₂), 3.04˜3.20 (3H, m, CH₂), 3.35˜3.50 (2H, m, CH₂and N—CH), 3.79 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 3.97 (1H, d, CH₂), 4.21 (2H, d, COCH₂), 5.08 (1H, brs, NH), 5.16 (1H, q, PhCH₂), 6.63 (1H, s, ArH), 6.76 (1H, s, ArH), 6.89 (1H, s, ArH), 7.29˜7.32 (1H, m, PhH), 7.35˜7.39 (2H, m, PhH), 7.45˜7.48 (2H, m, PhH).
Method B:
t-Boc-glycine (0.236 g, 1.35 mmol) was) was dissolved in dry CH₂Cl₂(10 ml), adding CDI (0.32 g, 1.98 mmol). The mixtured was stirred at room temperature for 1 hours and added the solution of compound IIA (0.25 g, 0.55 mmol) in CH₂Cl₂(10 ml). The mixture was stirred for 24 hours, followed evaporating under reduced pressure and purifying by Al₂O₃chromatography to give desired product.
Method C:
t-Boc-glycine (0.29 g, 1.66 mmol), EDCI (0.44 g, 2.2 mmol) and HOBt (0.3 g, 2.2 mmol) was dissolved in THF (10 ml) and stirred at room temperature for 30 minutes. After adding the solution of compound IIA (0.5 g, 1.1 mmol) in THF (10 ml), the mixture was stirred at room temperature for 24 hours. Then the mixture was evaporated under reduced pressure and dissolved in CH₂Cl₂. The solution was washed with saturated NH₄Cl, saturated NaHCO₃and brine, then dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give foam solid (0.476 g, 70.8%).

Example 27

2-benzyloxy-3,10-dimethoxy-9-glycyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Method A:
A product obtained in Example 26 (0.1 g, 0.16 mmol) was treat with 10% CF₃COOH in CH₂Cl₂. The mixture was evaporated under reduced pressure to give desired product.
Method B:
A product obtained in Example 26 (0.1 g, 0.16 mmol) was dissolved CH₂Cl₂, followed by treating with p-methylphenylsulfonic acid (0.055 g). The mixture was stirred at room temperature, followed by pouring into water. The aqueous phase was adjust to pH 8 with saturated NaHCO₃and extracted with CH₂Cl₂. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give desired product.

Example 28

2-hydroxy-3,10-dimethoxy-9-(N-t-Boc-glycyloxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 26 (0.1 g, 0.16 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give yellow powder (0.021 g, 24.6%). mp 213-214° C. ¹HNMR (CDCl₃+CD₃OD) δ: 1.41 (9H, s, 3×CH₃), 2.48˜2.66 (3H, m, CH₂), 2.97˜3.18 (2H, m, CH₂), 3.34˜3.47 (3H, m, CH₂and N—CH), 3.74 (3H, s, Ar—OCH₃), 3.78 (3H, s, Ar—OCH₃), 3.99 (1H, d, CH₂), 4.04 (2H, s, COCH₂), 5.08 (1H, brs, NH), 6.59 (1H, s, ArH), 6.73 (1H, s, ArH), 6.97 (1H, s, ArH), 7.69 (1H, s, Ar—OH).

Example 29

2-hydroxy-3,10-dimethoxy-9-glycyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 28 was treat with 10% CF₃COOH in CH₂Cl₂. The desired product was obtained following the synthetic procedure described in Example 23.

Example 30

2,9-bis-(N-t-Boc-valyloxy)-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 1 (0.1 g, 0.28 mmol), t-Boc-valine (0.32 g, 1.47 mmol), DCC (0.23 g, 1.1 mmol), DMAP (0.034 g, 0.28 mmol) and CH₂Cl₂(10 ml) was mixed and stirred at room temperature for 24 hours. The mixture was then cooled in refrigeratory. After filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow solid (0.146 g, 69.5%). mp 108˜110° C. ¹HNMR (CDCl₃) δ: 1.04 (6H, d, 2×CH₃), 1.10 (6H, q, 2×CH₃), 1.47 (18H, d, 6×CH₃), 2.33˜2.43 (2H, m, CH₂), 2.61˜2.74 (3H, m, CH₂), 3.13˜3.17 (2H, m, CH₂and CH), 3.28˜3.56 (3H, m, CH₂and N—CH), 3.77 (3H, s, Ar—OCH₃), 3.79 (3H, s, Ar—OCH₃), 4.03 (1H, d, CH₂), 4.52 (2H, m, COCH), 6.69 (1H, s, ArH), 6.89 (1H, s, ArH), 6.98 (1H, d, ArH).

Example 31

2,9-divalyloxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 30 (0.1 g, 0.13 mmol) was treat with 10% CF₃COOH in CH₂Cl₂. The desired product was obtained following the synthetic procedure described in Example 23.

Example 32

(−)-2,10-bis-(N-t-Boc-valyloxy)-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

l-SPD (0.09 g, 0.27 mmol), t-Boc-valine (0.144 g, 0.66 mmol), DCC (0.189 g, 0.92 mmol), DMAP (0.049 g, 0.4 mmol) and CH₂Cl₂(10 ml) was mixed and stirred at room temperature for 48 hours. The mixture was then cooled in refrigeratory. After filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow solid (0.115 g, 57.6%). ¹HNMR (CDCl₃) δ: 1.02˜1.03 (6H, d, 2×CH₃), 1.08˜1.11 (6H, q, 2×CH₃), 1.46˜1.48 (18H, d, 6×CH₃), 2.36˜2.42 (2H, m, CH₂), 2.63˜2.75 (2H, m, CH₂), 2.83˜2.89 (1H, m, CH₂), 3.14˜3.24 (3H, m, CH₂and CH), 3.53˜3.57 (2H, m, CH₂and N—CH), 3.78 (3H, s, Ar—OCH₃), 3.79 (3H, s, Ar—OCH₃), 4.18 (1H, d, CH₂), 4.52 (1H, d, COCH), 4.54 (1H, d, COCH), 6.70 (1H, s, ArH), 6.91 (3H, m, ArH).

Example 33

(−)-2,10-divalyloxy-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 32 (0.1 g, 0.14 mmol) was treat with 10% CF₃COOH in CH₂Cl₂. The desired product was obtained following the synthetic procedure described in Example 23.

Example 34

2,9-diacetoxy-3,10-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 2 (0.1 g, 0.27 ml) was dissolved in pyridine (10 ml), adding acetyl anhydride (0.5 ml). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and added water. Then the aqueous phase was adjust to pH 8 with saturated NaHCO₃and extracted with CH₂Cl₂. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to give pale desired product (0.073 g, 64.6%). mp 212˜214° C. ¹HNMR (CDCl₃) δ: 2.33 (3H, s, COCH₃), 2.34 (3H, s, COCH₃), 2.63˜2.75 (3H, m, CH₂), 3.13˜3.20 (3H, m, CH₂), 3.41˜3.56 (2H, m, CH₂and N—CH), 3.81 (3H, s, Ar—OCH₃), 3.82 (3H, s, Ar—OCH₃), 4.02 (1H, d, CH₂), 6.70 (1H, s, ArH), 6.83 (1H, d, ArH), 6.92 (1H, s, ArH), 7.00 (1H, s, ArH).

Example 35

2-benzyloxy-3,10-dimethoxy-9-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.5 g, 1.1 mmol), Cl(CH₂CH₂O)₃H (0.61 g, 3.6 mmol), K₂CO₃(0.31 g, 2.2 mmol) and DMF (15 ml) was mixed and heat to 100° C. for 20 hours. After filtering K₂CO₃, the mixture was concentrated to remove DMF, followed by pouring into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give yellow powder (0.418 g, 65.1%). The analytic sample was recrystallized with ethyl acetate/petroleum ether. ¹HNMR (CDCl₃) δ: 2.44˜2.68 (3H, m, CH₂), 3.10˜3.25 (3H, m, CH₂), 3.37˜3.59 (12H, m, CH₂and N—CH), 3.82 (3H, s, Ar—OCH₃), 3.87 (3H, s, Ar—OCH₃), 4.20˜4.24 (2H, m, OCH₂), 4.39 (1H, d, CH₂), 5.16 (2H, q, PhCH₂), 6.62 (1H, s, ArH), 6.77 (1H, s, ArH), 6.83 (1H, s, ArH), 7.26˜7.40 (3H, m, PhH), 7.45˜7.47 (2H, m, PhH).

Example 36

2-benzyloxy-3,10-dimethoxy-9-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.5 g, 1.1 mmol), Cl(CH₂CH₂O)₃CH₃(0.66 g, 3.6 mmol), K₂CO₃(0.31 g, 2.2 mmol) and DMF (15 ml) was mixed and heat to 100° C. for 20 hours. After filtering K₂CO₃, the mixture was concentrated to remove DMF, followed by pouring into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ethereum ether) to give yellow powder (0.43 g, 65.3%). The analytic sample was recrystallized with ethyl acetate/petroleum ether. ¹HNMR (CDCl₃) δ: 2.44˜2.69 (3H, m, CH₂), 3.07˜3.23 (3H, m, CH₂), 3.37˜3.61 (12H, m, CH₂and N—CH), 3.69 (3H, s, OCH₃), 3.82 (3H, s, Ar—OCH₃), 3.87 (3H, s, Ar—OCH₃), 4.06˜4.14 (1H, m, OCH₂), 4.17˜4.23 (1H, m, OCH₂), 4.23˜4.31 (1H, d, CH₂), 5.16 (2H, q, PhCH₂), 6.63 (1H, s, ArH), 6.79 (1H, s, ArH), 6.83 (1H, s, ArH), 7.25˜7.41 (3H, m, PhH), 7.45˜7.47 (2H, m, PhH).

Example 37

2-benzyloxy-3,10-dimethoxy-9-ethoxyoxalyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.2 g, 0.44 mmol) was dissolved in pyridine (10 ml), adding ClCOCOOC₂H₅(0.25 ml, 0.66 mmol) under ice bath. The mixture was stirred at room temperature overnight. Then the mixture was concentrated to small volume and added CH₂Cl₂. After filtering, the filtrate was washed with water, saturated NaHCO₃and brine. The solution was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=1/3) to give desired product (0.11 g, 45.2%). ¹HNMR (CDCl₃) δ: 1.32 (3H, s, CH₂CH₃) 2.46˜2.69 (3H, m, CH₂), 3.02˜3.20 (3H, m, CH₂), 3.49˜3.61 (2H, m, CH₂and N—CH), 3.87 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.06˜4.14 (2H, m, OCH₂), 4.23 (1H, d, CH₂), 5.17 (2H, q, PhCH₂), 6.65 (1H, s, ArH), 6.74 (1H, s, ArH), 6.91 (1H, s, ArH), 7.29˜7.35 (3H, m, PhH), 7.45˜7.49 (2H, m, PhH).

Example 38

2,9-diundecanoyloxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 1 (0.2 g, 0.55 mmol) was suspend on CH₂Cl₂(20 ml), adding hendecyl chloride (0.50 ml, 1.85 mmol) and triethylamine (0.24 ml). The mixture was stirred at room temperature for 7 hours. Then the mixture was poured into water, adjusting to pH 9 with saturated NaHCO₃. The aqueous phase was extracted with CH₂Cl₂. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give yellow oil (0.19 g, 49.3% 0. ¹HNMR (CDCl₃) δ: 0.97 (6H, 2 s, 2CH₃), 1.31˜1.55 (32H, m, CH₂), 2.11˜2.23 (4H, m, CH₂), 2.61˜2.75 (3H, m, CH₂), 3.13˜3.16 (2H, m, CH₂), 3.28˜3.41 (2H, m, CH₂), 3.55˜3.57 (1H, m, CH₂and N—CH), 3.80 (3H, s, Ar—OCH₃), 3.81 (3H, s, Ar—OCH₃), 3.96 (1H, d, CH₂), 6.73 (1H, s, ArH), 6.92 (1H, s, ArH), 6.96 (1H, s, ArH).

Example 39

2-benzyloxy-3,10-dimethoxy-9-undecanoyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.15 g, 0.33 mmol) was dissolved in pyridine (7 ml), adding hendecyl chloride (0.2 ml, 0.75 mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated to remove pyridine and the residue added CH₂Cl₂. After filtering the insoluble solid, the filtrate was washed with water, saturated NaHCO₃and brine. The solution was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give yellow oil (0.16 g, 78.2%). ¹HNMR (CDCl₃) δ: 0.95 (3H, s, CH₃), 1.32˜1.56 (16H, m, CH₂), 2.12˜2.21 (2H, m, CH₂), 2.46˜2.68 (3H, m, CH₂), 3.02˜3.21 (3H, m, CH₂), 3.49˜3.62 (2H, m, CH₂and N—CH), 3.89 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.24 (1H, d, CH₂), 5.18 (2H, q, PhCH₂), 6.66 (1H, s, ArH), 6.74 (1H, s, ArH), 6.92 (1H, s, ArH), 7.29˜7.36 (3H, m, PhH), 7.43˜7.48 (2H, m, PhH).

Example 40

2-benzyloxy-3,10-dimethoxy-9-(undec-10-enyloxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.15 g, 0.33 mmol) was dissolved in pyridine (7 ml), adding undec-10-enoyl chloride (0.2 ml, 0.74 mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated to remove pyridine and the residue added CH₂Cl₂. After filtering the insoluble solid, the filtrate was washed with water, saturated NaHCO₃and brine. The solution was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give yellow oil (0.15 g, 73.2%). ¹HNMR (CDCl₃) δ: 1.32˜1.56 (14H, m, CH₂), 2.12˜2.21 (2H, m, CH₂), 2.46˜2.68 (3H, m, CH₂), 3.02˜3.21 (3H, m, CH₂), 3.49˜3.62 (2H, m, CH₂and N—CH), 3.89 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.24 (1H, d, CH₂), 4.89˜5.10 (2H, m, C═CH₂), 5.18 (2H, q, PhCH₂), 5.32 (1H, m, C═CH) 6.66 (1H, s, ArH), 6.74 (1H, s, ArH), 6.92 (1H, s, ArH), 7.29˜7.36 (3H, m, PhH), 7.43˜7.48 (2H, m, PhH).

Example 41

2-hydroxy-3,10-dimethoxy-9-undecanoyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 39 (0.07 g, 0.1 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The product was given as pale brown oil (0.05 g, 85.8%). ¹HNMR (CDCl₃) δ: 0.95 (3H, s, CH₃), 1.32˜1.56 (16H, m, CH₂), 2.12˜2.21 (2H, m, CH₂) 2.58˜2.70 (3H, m, CH₂), 3.04˜3.24, 3.38˜3.39 (3H, m, CH₂), 3.54˜3.66 (2H, m, CH₂and N—CH), 3.87 (3H, s, Ar—OCH₃), 3.88 (3H, s, Ar—OCH₃), 4.25 (1H, d, CH₂), 5.52 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.87 (1H, s, ArH), 6.93 (1H, s, ArH).

Example 42

2,9-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy-}3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 1 (0.22 g, 0.61 mmol) suspend on CH₂Cl₂(22 ml), adding CH₃(OCH₂CH₂)₂OCH₂COCl (0.25 ml, 1.81 mmol) and triethylamine (0.24 ml). The mixture was stirred at room temperature for 15 hours. Then the mixture was poured into water and extracted with CH₂Cl₂. The combined organic layers were washed with saturated NaHCO₃and brine. The solution was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give yellow oil (0.19 g, 45.3%). ¹HNMR (CDCl₃) δ: 2.61˜2.75 (3H, m, CH₂), 3.13˜3.26 (3H, m, CH₂), 3.28˜3.41 (6H, m, CH₃), 3.51˜3.75 (18H, m, CH₂and N—CH), 3.80 (3H, s, Ar—OCH₃), 3.81 (3H, s, Ar—OCH₃), 3.96 (1H, d, CH₂), 4.16˜4.35 (4H, m, OCH₂) 6.73 (1H, s, ArH), 6.92 (1H, s, ArH), 6.96 (1H, s, ArH).

Example 43

2-hydroxy-3,10-dimethoxy-9-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy-}-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound IIA (0.2 g, 0.44 mmol) was dissolved in pyridine (10 ml), adding CH₃(OCH₂CH₂)₂OCH₂COCl (0.2 ml, 0.72 mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated to remove pyridine and the residue was added CH₂Cl₂. After filtering the insoluble solid, the filtrate was washed with water, saturated NaHCO₃and brine. The solution was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give 2-hydroxy-3,10-dimethoxy-9-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy}-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine. The compound is yellow oil (0.23 g, 84.2%). ¹HNMR (CDCl₃) δ: 2.61˜2.75 (3H, m, CH₂), 3.13˜3.26 (3H, m, CH₂), 3.28˜3.41 (3H, m, CH₃), 3.51˜3.75 (10H, m, CH₂and N—CH), 3.80 (3H, s, Ar—OCH₃), 3.81 (3H, s, Ar—OCH₃), 3.96 (1H, d, CH₂), 4.16˜4.35 (2H, m, OCH₂), 5.18 (2H, q, PhCH₂), 6.73 (1H, s, ArH), 6.92 (1H, s, ArH), 6.96 (1H, s, ArH), 7.29˜7.36 (3H, m, PhH), 7.43˜7.48 (2H, m, PhH).
The product obtained above was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7.

Example 44

2,3,9,10-tetrahydroxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 1 (0.3 g, 0.66 mmol) was dissolved in CH₂Cl₂(20 ml), adding a solution of BBr₃(0.32 ml) in CH₂Cl₂(5 ml) under ice-salt bath. The mixture was stirred for 1 hours at this temperature, then stirred at room temperature overnight. The reactant solution produced yellow precipitate. The mixture was poured into water and stirred for 30 minute. After filtering, the solid was dissolved with methanol. Then the mixture was filtered. The filtrate was evaporated under reduced pressure, followed by recrystallizing with methanol to give yellow solid (0.15 g, 67.7%). mp 295˜296° C. ¹HNMR (DMSO-d₆) δ: 2.65˜2.86 (3H, m, CH₂), 3.05˜3.63 (5H, m, CH₂or N—CH), 4.29 (1H, d, CH₂), 6.59 (1H, s, ArH), 6.81 (1H, s, ArH), 6.92 (1H, s, ArH). MS (EI) m/z: 333 (M⁺), 299, 164 (base), 107, 80.

Example 45

2-hydroxy-3,10-dimethoxy-9-(2-hydroxy-ethoxy)-12-chloro-N-methyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 17 (0.1 g) was dissolved in THF (20 ml), adding iodomethane (0.1 ml). The mixture was stirred at room temperature overnight. The yellow solid precipitating was filtered and dried to give yellow powder.

Example 46

(−)-2-hydroxy-3,10-dimethoxy-9-valyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound (−)-IIA (preparation as the method reported in CN03151464.2) was treat with N-CBz-L-valine. According the procedure described in method C of Example 26, compound (−)-2-benzyloxy-9-O-(t-Boc-valine)acyl-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine was obtained. This compound was debenzyl with Pd—C/H₂(the method described in Example 2). Then the crude product was purified by silica chromatography to give desired product.

Example 47

(−)-2,9-diacetoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound (−)-IIA was hydrogenated in the present of Raney-Ni according the procedure described in Example 1 to give (−)-2,9-dihydroxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine. This compound was acetylation with acetyl anhydride according the method described in Example 6 to give desired product. The total yield is 81%. mp 202˜203° C. Anal: Cacl: C, 61.95%; H, 5.43%; N, 3.14%; test: C, 62.18%; H, 5.35%; N, 3.06%. [α]²⁵ _D=−254°(C=0.2, CHCl₃). ¹HNMR (CDCl₃) δ: 2.34 (6H, 2 s, 2×COCH₃), 2.58˜2.76 (3H, m, CH₂), 3.11˜3.17 (2H, m, CH₂), 3.28˜3.43 (2H, m, CH₂), 3.55 (1H, dd, N—CH), 3.80 (3H, s, Ar—OCH₃), 3.82 (3H, s, Ar—OCH₃), 3.99 (1H, d, CH₂), 6.71 (1H, s, ArH), 6.91 (1H, s, ArH), 6.97 (1H, s, ArH). MS (EI) m/z: 445 (M⁺), 444 (M−1), 386 (base), 184, 176, 77.

Example 48

(−)-2,10-diacetoxy-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

l-SPD (0.264 g, 0.81 mmol), pyridine (1 ml) and acetyl anhydride (0.5 ml) was mixtured and stirred at room temperature for 0.5 hours. The mixture was poured into water, then yellow solid was precipitated. The solid was collected by filtering and wash with water, then dried at 40° C. to give pale yellow solid (0.235 g, 70.8%). Anal: cacl: C, 67.14%; H, 6.12%; N, 3.40%; test: C, 67.46%; H, 5.97%; N, 3.30%. ¹HNMR (CDCl₃) δ:2.32 (6H, 2 s, 2×COCH₃), 2.61˜2.91 (3H, m, CH₂), 3.14˜3.29 (3H, m, CH₂), 3.51˜3.60 (2H, m, CH₂and N—CH), 3.81 (3H, s, Ar—OCH₃), 3.82 (3H, s, Ar—OCH₃), 4.20 (1H, d, J=15.9 Hz, CH₂), 6.71 (1H, s, ArH), 6.90 (2H, s, ArH), 6.92 (1H, s, ArH). MS (EI) m/z: 411 (M⁺), 368, 220, 176, 150 (base), 135.

Example 49

(−)-2-benzyloxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Starting from compound (−)-IIA, the desired product was obtained following the synthetic procedure described in Example 6 to give white powder. It can be used in next step without purification.

Example 50

(−)-2-hydroxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Starting from the product obtained in Example 49, the desired product was obtained following the synthetic procedure described in Example 7 to give pink powder. The total yield from compound IIA was 63.26%. mp 172˜173° C. Anal: calcd: C, 62.45%; H, 5.49%; N, 3.47%; test: C, 62.31%; H, 5.33%; N, 3.28%. [α]²⁵ _D=−235° (CHCl₃). MS (EI) m/z: 405 (M+2), 403 (M⁺), 360, 344 (base), 186, 149, 91.

Example 51

(−)-2,9-bis-(N-benzyloxycarbonyl-valyloxy)-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound (−)-IIA was hydrogenated in the present of Raney-Ni according the procedure described in Example 1 to give (−)-2,9-dihydroxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine.
The methanesulfonate of this compound (0.6 g, 1.3 mmol), N-CBz-valine (1.32 g, 5.26 mmol), DCC (1.08 g, 5.24 mmol) and DMAP (0.16 g, 1.31 mmol) was mixed with CH₂Cl₂(20 ml) and stirred at room temperature for 6 hours. Then the mixture was cooled in refrigeratory. After filtered, the filtrate was evaporated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow solid (1.01 g, 93.1%). The analytic sample was recrystallized with ethyl acetate/petroleum ether. ¹HNMR (CDCl₃) δ: 1.04 (6H, d, 2×CH₃), 1.11 (6H, d, 2×CH₃), 2.40˜2.47 (2H, m, CH₂), 2.60˜2.74 (3H, m, CH₂), 3.09˜3.15 (2H, m, CH₂and CH), 3.29˜3.57 (3H, m, CH₂and N—CH), 3.76 (3H, s, Ar—OCH₃), 3.78 (3H, s, Ar—OCH₃), 3.98 (1H, d, J=12 Hz, CH₂), 4.62 (2H, m, COCH), 5.16 (4H, s, OCH₂Ph), 5.34 (1H, d, NH), 5.39 (1H, d, NH), 6.69 (1H, s, ArH), 6.89 (1H, s, ArH), 6.95 (1H, d, ArH), 7.32˜7.40 (10H, m, PhH).

Example 52

(−)-2-benzyloxy-3,10-dimethoxy-9-ethoxycarbonylmethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound (−)-IIA (1.0 g, 2.2 mmol) was dissolved in dry DMF (10 ml), adding BrCH₂COOC₂H₅(0.27 ml, 2.4 mmol), K₂CO₃(0.61 g, 4.4 mmol). The mixture was stirred at room temperature for 6 hours. After filtering K₂CO₃, the filtrate was concentrated to remove DMF, followed by adding water. The aqueous phase was extracted two times with CH₂Cl₂. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved with ethyl acetate and filtered. The filtrate was recrystallized with ethyl acetate/petroleum ether to give white powder (0.4 g, 34%).

Example 53

2-benzyloxy-3,10-dimethoxy-9-ethoxycarbonylmethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

The desired product was obtained following the synthetic procedure described in Example 52. The crude product was purified by silica chromatography to give milk white powder. mp 134° C. ¹HNMR (CDCl₃) δ:1.31 (3H, t, CH₃), 2.46˜2.70 (3H, m, CH₂), 3.10˜3.21 (3H, m, CH₂), 3.46 (1H, dd, N—CH₂), 3.53 (1H, d, CH₂), 3.81 (1H, s, Ar—OCH₃), 3.88 (1H, s, Ar—OCH₃), 4.26 (2H, q, OCH ₂CH₃), 4.35 (1H, d, CH₂), 4.63 (2H, q, OCH₂CO), 5.16 (2H, q, PhCH₂O), 6.64 (1H, s, ArH), 6.78 (1H, s, ArH), 6.84 (1H, s, ArH), 7.27˜7.40 (3H, m, PhH), 7.45˜7.48 (2H, m, PhH).

Example 54

(−)-2-hydroxy-3,10-dimethoxy-9-ethoxycarbonylmethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Starting from the product obtained in Example 52, the desired product was obtained following the synthetic procedure described in Example 1 to give pale yellow powder. The analytic sample was recrystallized with ethyl acetate/petroleum ether. mp 202˜204° C. ¹HNMR (CD₃OD) δ:1.26 (3H, t, CH₃), 2.84˜3.11 (2H, m, CH₂), 3.22˜3.34 (4H, m, CH₂), 3.55 (1H, td, N—CH), 3.71˜3.82 (1H, d, CH₂), 3.86 (1H, s, Ar—OCH₃), 3.88 (1H, s, Ar—OCH₃), 4.20 (2H, q, OCH₂CH₃), 4.50 (1H, d, CH₂), 4.76 (2H, q, OCH₂CO), 5.07 (2H, q, PhCH₂), 6.83 (1H, s, ArH), 6.85 (1H, s, ArH), 7.21 (1H, s, ArH).

Example 55

2-hydroxy-3,10-dimethoxy-9-ethoxycarbonylmethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Starting from the product obtained in Example 53, the desired product was obtained following the synthetic procedure described in Example 54 to give milk white powder. mp 132° C.

Example 56

(−)-2-hydroxy-3,10-dimethoxy-9-carboxymethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 54 (1.92 g, 4.3 mmol) was dissolved in ethanol (20 ml), adding NaOH (0.343 g, 8.6 mmol, dissolved in 10 ml water). The mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated under reduced pressure followed by adding water. The aqueous phase was washed with ethyl acetate and adjust to pH 3˜4 by 1 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed by water. Recrystallizing with methanol/water to give yellow powder (1.11 g, 62%). mp 179˜180° C. [α]²⁵ _D=−149° (CH₃OH). ¹HNMR (DMSO-d₆) δ:2.40˜2.50 (2H, m, CH₂), 2.65˜2.76 (2H, m, CH₂), 2.91˜2.99 (1H, m, CH₂), 3.30˜3.56 (3H, m, CH₂and N—CH), 3.74 (1H, s, Ar—OCH₃), 3.80 (1H, s, Ar—OCH₃), 4.41 (1H, d, CH₂), 4.63 (2H, q, OCH₂CO), 6.69 (1H, s, ArH), 6.76 (1H, s, ArH), 7.12 (1H, s, ArH).

Example 57

2-hydroxy-3,10-dimethoxy-9-carboxymethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

A product obtained in Example 55 (3.1 g, 6.9 mmol) was dissolved in ethanol (50 ml), adding 1 mol/L NaOH (13.9 ml). The mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated under reduced pressure followed by adding water. The aqueous phase was washed with ethyl acetate and adjust to pH 5˜6 by 1 mol/L hydrochloric acid. The precipitated solid was collected by filtration and washed by water to give pale yellow powder. The solid was dissolved in alkali solution and adjust the pH again to give the refine product (2.6 g, 89.5%). mp 172˜174° C. ¹HNMR (DMSO-d₆) δ: 2.30˜2.49 (2H, m, CH₂), 2.58˜2.63 (1H, d, CH₂), 2.89˜2.95 (1H, m, CH₂), 3.08 (1H, dd, CH₂), 3.23 (1H, dd, N—CH), 3.38˜3.47 (2H, m, CH₂), 3.74 (3H, s, Ar—OCH₃), 3.79 (1H, s, Ar—OCH₃), 4.25 (1H, d, CH₂), 4.59 (2H, q, OCH₂CO), 6.66 (1H, s, ArH), 6.73 (1H, s, ArH), 7.05 (1H, s, ArH).

Example 58

2-benzyloxy-3,10-dimethoxy-9-carboxymethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Starting from the product obtained in Example 53 (0.32 g, 0.59 mmol), the desired product was obtained following the synthetic procedure described in Example 57 to give pale yellow powder (0.22 g, 73.7%). ¹HNMR (DMSO-d₆) δ: 2.30 (1H, dd, CH₂), 2.58˜2.69 (2H, m, CH₂), 2.89˜2.95 (1H, m, CH₂), 3.14 (1H, d, CH₂), 3.32 (1H, dd, N—CH), 3.39˜3.49 (2H, m, CH₂), 3.74 (3H, s, Ar—OCH₃), 3.79 (1H, s, Ar—OCH₃), 4.30 (1H, d, CH₂), 4.61 (2H, q, OCH₂CO), 5.07 (2H, s, OCH₂Ph), 6.73 (1H, s, ArH), 6.98 (1H, s, ArH), 7.07 (1H, s, ArH), 7.29˜7.48 (5H, s, PhH).
Starting from the product descried above (Example 58), the product in Example 57 was also obtained following the synthetic procedure described in Example 55.

Example 59

(−)-2,9-diethoxycarbonylmethoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound (−)-IIA was hydrogenated in the present of Raney-Ni according to the procedure described in Example 1 to give (−)-2,9-dihydroxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine.
The compound described above (3.3 g, 9.1 mmol) was dissolved in dry DMF (10 ml), adding BrCH₂COOC₂H₅(2.53 ml) and K₂CO₃(3.78 g). The mixture was stirred at room temperature for 2 hours. After filtering K₂CO₃, the filtrate was concentrated to remove DMF, followed by diluting with water. The aqueous phase was extracted two times with CH₂Cl₂. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give compounds 59a, 59b and 59c.

59a: (−)-2,9-diethoxycarbonylmethoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Crude compound 59a was recrystallized with ethyl acetate/petroleum ether to give desired white powder (1.3 g, 26.7%). ¹HNMR (CD₃Cl) δ: 1.31 (6H, t, CH₃×2), 2.55˜2.71 (3H, m, CH₂), 3.08˜3.32 (3H, m, CH₂), 3.48˜3.57 (2H, m, CH₂and N—CH), 3.81 (3H, s, Ar—OCH₃), 3.87 (3H, s, Ar—OCH₃), 4.22˜4.33 (4H, m, OCH ₂CH₃×2), 4.37 (1H, d, CH₂), 4.55˜4.75 (4H, q, OCH₂CO×2), 6.64 (1H, s, ArH), 6.79 (1H, s, ArH), 6.84 (1H, s, ArH).

59b: (−)-2,9-diethoxycarbonylmethoxy-3,10-dimethoxy-12-chloro-N-α-ethoxycarbonylmethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound 59b (0.15 g, 2.3%) was yellow powder. ¹HNMR (CD₃Cl) δ: 1.28 (9H, m, CH₃×3), 2.84 (1H, m, CH₂), 3.17˜3.25 (2H, m, CH₂), 3.42˜3.64 (2H, m, CH₂), 3.84 (3H, s, Ar—OCH₃), 3.89 (3H, s, Ar—OCH₃), 4.16˜4.31 (6H, m, OCH ₂CH₃×3), 4.59 (1H, m, CH₂), 4.65 (2H, m, OCH₂CO), 4.71 (2H, s, NCH₂CO), 4.95 (1H, d, CH₂or N—CH), 5.44 (1H, d, CH₂), 5.68 (2H, q, OCH₂CO), 6.13 (1H, m, CH₂), 6.74 (1H, s, ArH), 6.82 (1H, s, ArH), 6.95 (1H, s, ArH).

59c: (−)-2,9-diethoxycarbonylmethoxy-3,10-dimethoxy-12-chloro-N-β-ethoxycarbonylmethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Compound 59c (0.2 g, 3.1%) was yellow powder. ¹HNMR (CD₃Cl) δ: 1.28 (9H, m, CH₃×3), 2.68˜2.78 (1H, m, CH₂), 3.01 (1H, m, CH₂), 3.26 (1H, m, CH₂), 3.72 (2H, m, CH₂), 3.85 (3H, s, Ar—OCH₃), 3.89 (3H, s, Ar—OCH₃), 4.11˜4.33 (6H, m, OCH ₂CH₃×3), 4.62 (2H, m, OCH₂CO), 4.72 (1H, m, CH₂), 4.81 (2H, s, NCH₂CO), 4.98 (1H, d, OCH₂CO), 5.22 (1H, d, CH₂or N—CH), 5.64 (1H, d, OCH₂CO), 5.93 (1H, d, CH₂), 6.49 (1H, m, CH₂), 6.73 (1H, s, ArH), 6.83 (1H, s, ArH), 7.00 (1H, s, ArH).

Example 60

2,9-diethoxycarbonylmethoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

The desired product was obtained following the synthetic procedure described in Example 59.

Example 61

(−)-2,9-dicarboxymethoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Starting from the product obtained in Example 59a (1.33 g, 2.49 mmol), the desired product was obtained following the synthetic procedure described in Example 56 to give yellow powder (0.653 g, 54.9%). mp 230˜232° C. ¹HNMR (DMSO-d₆) δ:2.24˜2.33 (1H, m, CH₂), 2.60˜2.64 (1H, d, CH₂), 2.86˜2.95 (1H, m, CH₂), 3.05 (1H, dd, CH₂), 3.26 (1H, dd, N—CH), 3.36˜3.42 (3H, m, CH₂), 3.74 (3H, s, Ar—OCH₃), 3.76 (1H, s, Ar—OCH₃), 4.25 (1H, d, CH₂), 4.51 (4H, s, OCH₂CO), 6.71 (1H, s, ArH), 6.81 (1H, s, ArH), 7.01 (1H, s, ArH). MS (EI) m/z: 478 (M⁺), 476 (M−2), 418 (base), 344, 183, 91, 77.

Example 62

2,9-dicarboxymethoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

Staring from the product obtained in Example 60, the desired product was obtained following the synthetic procedure described in Example 61 to give yellow powder. Yield: 90%. mp 202˜204° C. ¹HNMR (DMSO-d₆) δ: 2.25˜2.34 (1H, m, CH₂), 2.60˜2.65 (1H, d, CH₂), 2.86˜2.90 (1H, m, CH₂), 3.05 (1H, dd, CH₂), 3.27 (1H, dd, N—CH), 3.37˜3.44 (3H, m, CH₂), 3.77 (3H, s, Ar—OCH₃), 3.78 (1H, s, Ar—OCH₃), 4.25 (1H, d, CH₂), 4.52 (4H, s, OCH₂CO), 6.71 (1H, s, ArH), 6.81 (1H, s, ArH), 7.02 (1H, s, ArH).

Example 63

2,3-methylenedioxyl-9,10-dimethoxy-12-fluoro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine

2,3-methylenedioxyl-9,10-dimethoxy-12-amino-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine (0.1 g, 0.28 mmol) was suspend on HBF₄(5 mL), cooling to −10° C. in ice-salt bath. A solution of NaNO₂(0.19 g) in water (1.5 mL) was dropped slowly to control the temperature <−8° C. When finished, the mixture was stirred in ice bath for 0.5˜1 hours, followed cooling in refrigeratory. The precipitate was collected by filtering and washed by cool water and cool ethanol to give pale yellow powder (0.12 g). The powder was pyrolyzed in 110° C. The crude product was purified by silica chromatography (CH₂Cl₂/methanol) to give pale yellow powder (0.05 g, 49.6%). ¹H NMR (CDCl₃) δ: 2.57˜2.69 (3H, m, CH₂), 3.13˜3.22 (2H, m, CH₂), 3.31 (1H, dd, CH₂), 3.34˜3.55 (2H, m, CH₂and N—CH), 3.80 (3H, s, Ar—OCH₃), 3.83 (3H, s, Ar—OCH₃), 4.23 (1H, d, CH₂), 5.92 (2H, s, OCH₂O), 6.56 (1H, s, Ar—H), 6.59 (1H, s, Ar—H), 6.76 (1H, s, Ar—H). MS (EI) m/z: 357 (M⁺), 326, 182, 167 (base), 149. MS (HR-EI) m/z: 357.1380 (M⁺); calcd: 357.1376.

Claims

1. Compounds of the formula (I), their stereoisomers, pharmacologically acceptable salts and solvates:

Wherein

R is H, halogen or cyano;

Each of R₁, R₃, R₄is selected from H, C₁˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, acyl (COR₇), SO₂R₆, SO₂NR₉R₁₀, or R₁and R₂together form (CH₂)_n, n is 1 or 2; when R₁, R₃, R₄is C₁˜C₁₂alkyl, the alkyl is saturated or unsaturated alkyl, linear chain C₁˜C₁₂alkyl, branched chain C₁˜C₁₂alkyl, C₁˜C₁₂cycloalkyl, C₁˜C₁₂alkyl substituted by aryl, COOR₆or CONR₉R₁₀; when R₁, R₃, R₄is amino acid or N-protected amino acid, which is D-, L- or DL-amino acid or N-protected amino acid; the protecting group is selected from Boc, Cbz or other protecting group used in amino acid; R₆is selected from H, C₁˜C₃alkyl or alkyl substituted by aryl; R₇is selected from C₁˜C₁₂alkyl, alkyl substituted by (CH₂CH₂O)_nR₆(n=1˜3), alkoxy, COR₈, (CH₂)_nNR₉R₁₀, substituted aryl, unsubstituted aryl, heterocyclic radical selected from imidazolyl, pyrazolyl, pyrrolidinyl, pyridinyl; when R₇is C₁˜C₁₂alkyl, the alkyl is saturated or unsaturated alkyl, linear chain C₁˜C₁₂alkyl, branched chain C₁˜C₁₂alkyl, C₁˜C₁₂cycloalkyl, C₁˜C₁₂alkyl substituted by carbonyl, phenyl, substituted phenyl or substituted aryl heterocyclic radical; R₈is selected from H, alkyl, alkoxy or aryl; R₉and R₁₀is selected independently from H, C₁˜C₄alkyl substituted by C₃-C₅cycloalkyl or C₁˜C₄alkoxy, or form heterocyclic radical selected from azacyclobutyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl with N;

R₂is selected from H, C₁˜C₃alkyl, or R₁and R₂together form (CH₂)_n, n is 1 or 2;

R₅is H, O, C₁˜C₃alkyl, substituted C₁˜C₃alkyl, halogen or aryl, or there is no existing of R₅;

Among the above compounds, when R═R₁═H and R₂═R₃═CH₃, R₄is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀;

When R═R¹═H and R₂═R₄═CH₃, R₃is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀;

When R═H and R₁═CH₃, R₂is CH₃, and one of R₃and R₄is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀;

When R═H and R₁═CH₂Ph, one of R₃and R₄is unsubstituted C₂˜C₁₂alkyl, substituted C₂˜C₁₂alkyl, (CH₂CH₂O)_nR₆(n=1˜3), amino acid or N-protected amino acid, COR₇, SO₂R₆or SO₂NR₉R₁₀;

When R═H and R₁and R₂together form CH₂, R₃or R₄can't be selected from H, CH₃, C₂H₅or COCH₃at the same time;

And when R=halogen, the said compounds exclude the following known compounds:

2,9-dihydroxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,10-dihydroxy-3,9-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,3,9,10-tetramethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,9-dihydroxy-3,10-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,10-dihydroxy-3,9-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

3,9-dihydroxy-2,10-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

9,10-dihydroxy-2,3-dimethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,3,9,10-tetramethoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,9-dihydroxy-3,10-dimethoxy-12-fluoro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,9-dihydroxy-3,10-dimethoxy-12-iodo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,3-methylenedioxyl-9-hydroxy-10-methoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,3-methylenedioxyl-9-hydroxy-10-methoxy-12-bromo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine.

2. The compounds according to claim 1, wherein R₁is H, COR₇, amino acid, or R₁and R₂together form CH₂; R₇is selected from C₁˜C₁₂alkyl, COR₈, alkoxy, or alkyl substituted by (CH₂CH₂O)_nR₆(n=1˜3); R₆is H, C₁˜C₃alkyl or alkyl substituted by aryl; R₈is alkoxy;

R₂is H, methyl, or R₂and R₁together form CH₂;

R₃is H, COR₇or amino acid;

R₄is H, methyl or amino acid;

R is H, Cl or F.

3. The compounds according to claim 1, wherein the said compounds of formula (I) are the following compounds:

2-hydroxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,9-diacetoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2-hydroxy-3,10-dimethoxy-9-(2-hydroxy-ethoxy)-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2-hydroxy-3,10-dimethoxy-9-ethoxycarbonyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2-benzyloxy-3,10-dimethoxy-9-phenylalanyloxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,9-diacetoxy-3,10-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,9-bis-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy}-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2-hydroxy-3,10-dimethoxy-9-{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxy}-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,3,9,10-tetrahydroxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

(−)-2,9-diacetoxy-3,10-dimethoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo [a,g]quinolizine;

(−)-2,10-diacetoxy-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

(−)-2-hydroxy-3,10-dimethoxy-9-acetoxy-12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine;

2,3-methylenedioxyl-9,10-dimethoxy-12-fluoro-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine.

4. The compounds according to claim 1, wherein the physiologically acceptable salts are salts of the compounds of formula (I) with acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, organic sulfonic acid; or salts of the compounds of formula (I) with alkali, especially alkali metal derivatives, including sodium or potassium derivatives.

5. The preparation method of the compounds according to claim 1:

(1) Preparation from formula (II):

Compound of formula (II) is reacted with compound of formula (III) to prepare compound of formula (I):

1) Compound of formula (II) is reacted with R₃Cl or R₃Br; the temperature is in the range of 0° C.-100° C., the reaction is catalysted by inorganic alkali or organic alkali, wherein the inorganic alkali is NaOH, KOH, CsOH, Ba(OH)₂, Mg(OH)₂, Ca(OH), KHCO₃, K₂CO₃, Na₂CO₃or Cs₂CO₃, the organic alkali is sodium alkoxide, NEt₃, N(C₄H₉)₃or N(C₃H₇)₃, the mixture was stirred at 0-100° C. for 2-24 hours to give compound of formula (I); the solvent is selected from the group including methanol, ethanol, isopropanol, C₄H₉OH, iso-C₄H₉OH, t-C₄H₉OH, C₅H₁₁H, iso-C₅H₁₁H, and the mixture of the above alcohol and water, in which alcohol:water=5:9.5-9.5:0.5 (V: V), or from the group including DMF, CH₂Cl₂, DMSO, THF, dioxane, pyrrolidone derivatives, acetone and CH₃OCH₂CH₂OCH₃;

2) Compound of formula (II) is reacted with R₃COCl, (R₃CO)₂O or (R₃CO)₂O; the reaction carry through in the present of inorganic alkali or organic alkali at 0-100° C., wherein the inorganic alkali is NaOH, KOH, CsOH, Ba(OH)₂, Mg(OH)₂, Ca(OH)₂, KHCO₃, K₂CO₃, Na₂CO₃or Cs₂CO₃, the organic alkali is pyridine, NEt₃, N(C₄H₉)₃, N(C₃H₇)₃; the mixture is stirred at 0-100° C. for 2-8 hours to give compound of formula (I); the solvent is selected in pyridine, DMF, CH₂Cl₂, DMSO, THF, dioxane and pyrrolidone derivatives; The catalyst DMAP is added according the reaction conditions;

3) Compound of formula (II) is reacted with ClSO₂R₆or ClSO₂NR₉R₁₀; The reaction carry through in the present of inorganic alkali or organic alkali at 0° C. to room temperature, wherein the inorganic alkali is NaOH, KOH, CsOH, Ba(OH)₂, Mg(OH)₂, Ca(OH)₂, KHCO₃, K₂CO₃, Na₂CO₃or Cs₂CO₃, the organic alkali is pyridine, NEt₃, N(C₄H₉)₃, N(C₃H₇)₃; the mixture was stirred at 0-100° C. for 2-8 hours to give compound of formula (I); The solvent can be selected in pyridine, DMF, CH₂Cl₂, DMSO, THF, dioxane and pyrolidinylone;

4) Compound of formula (II) is reacted with N-protected amino acid; The reaction of THPBs with amino acid is finished through the procedure of esterification from the acylchloride derivatives of amino acid to give the desired compound; another method is treat THPBs and amino acid in the present of amino acid catalyst; the reaction is carried through at 0° C. to room temperature to give compound of formula (I); the solvent is selected in CH₂Cl₂, DMF or THF; The catalyst is selected in DCC, CDI, EDCI or other coupled reagent, accompanied by HOBt or DMAP;

5) The deprotection of N-protected amino acid derivatives of THPBs (II) is carried through in the present of inorganic acid or organic acid at 0° C. to room temperature, wherein the inorganic acid is HCl or H₂SO₄, the organic acid is toluenesulfonic acid, CF₃COOH or AcOH; The solvent is selected in CH₂Cl₂or THF;

6) When R₁═H, compound of formula (I) is obtained by hydrogenating the compound of formula (II) (R₁═CH₂Ph) in the present of catalyst at 0-40° C. for 1-10 h; the catalyst is Raney-Ni, the solvent is methanol, ethanol, isopropanol or the mixture solution of the above alcohol and water;

(2) Preparation from formula (IV):

Compound of formula (IV) is reacted with compound of formula (III) to prepare the compound of formula (I):

R₁Y (or R₃Y) (III)

1) Compound of formula (IV) is reacted with R₁Cl or R₁Br in different ratio of amount to give compound of formula (I); 2) Compound of formula (IV) is reacted with R₁COCl, (R₁CO)₂O or (R₃CO)₂O in different ratio of amount to give compound of formula (I);

(3) Preparation from formula (V):

Compound of formula (V) is l-SPD. Staring from l-SPD, the compound of formula (I) is provided by esterification, etherification, coupling with amino acid or demethylation;

(4) The preparation of N-substituted derivatives of formula (I):

The free base of compound of formula (I) is reacted with alkyl halide or substituted alkyl halide at room temperature to 100° C., followed by precipitating when cooling, or by separating through column chromatography to give the target product;

(5) Preparation from formula (VI):

Compound of formula (VI) is treated with HNO₂to give diazo salt, which is reacted with corresponding reagent to give the compound of formula (I) (R=halogen, CN).

6. The preparation method according to claimed 5, wherein the benzylosy derivatives of compound of formula (I) is debenzylated in the present of Raney-Ni at 0-40° C. for 1-10 hours to give compound of formula (I); the solvent is alcohol, or the mixture solution of alcohol and water.

7. The preparation method according to claimed 5, wherein compound of formula (II) is reacted with N-protected amino acid in the present of amino acid catalyst at 0° C. to room temperature to give compound of formula (I); the solvent is selected from CH₂Cl₂, DMF or THF; the catalyst is selected from DCC, CDI or EDCI or other coupled reagent, accompanied by HOBt or DMAP.

8. The use of the compound according to claim 1 in the preparation of the medicines for prevention or treatment of the disease of the central nervous system.

9. The use according to claim 8, wherein the disease of the central nervous system is schizophrenia, parkinsonism, hyperactivity disorder or migraine.